Chronic Myelomonocytic Leukemia (CMML) is a lethal subtype of leukemia characterized by cytopenias, marrow dysplasia, monocytosis, and a propensity for transformation to acute myeloid leukemia (AML). It is among the most aggressive chronic myeloid malignancies with a median survival of 34 months. Recurrent mutations in CMML have been identified in over 40 genes affecting chromatin state, mRNA splicing, hematopoietic differentiation, and cytokine signaling pathways. Unfortunately, despite the increasing number of genetic alterations identified in CMML, no therapies have been developed with the potential to improve the poor natural history of CMML. Moreover, attempts to model CMML using genetically engineered mouse models have not recapitulated the unique clinical or histological characteristics of the human disease. Patient-derived xenografts (PDX) of acute leukemias have been created using immunocompromised mouse hosts that accurately model the disease and have been used to credential putative therapeutic targets in vivo. However, until now, there has been limited success with development of PDX models for CMML. Recently, our groups have overcome this limitation and generated highly and genetically accurate PDX models of CMML through the use of several novel modified NOD/SCID IL2R? null (NSG) mouse strains expressing human cytokines that uniquely drive CMML. Moreover, we have utilized these PDX models to identify novel therapies targeting aberrant cytokine-signaling characteristics and mRNA splicing in specific genetic subsets of CMML. In this proposal we aim to further define the fidelity of these models to the human condition and test several novel preclinical therapeutic approaches with immediate translatability to CMML patients as follows: In Aim 1 we will rigorously explore the fidelity of our PDX models compared to their respective patients by determining if PDX models recapitulate the entire clinical, transcriptional, and proteomic spectrum of CMML ; Aim 2 will determine whether CMML PDX models can recapitulate patient-specific responses to JAK2 inhibitors using samples from both our completed phase I/II clinical trial of the JAK1/2 inhibitor ruxolitinib in CMML and a prospective phase 2 ruxolitinib CMML clinical study; Aim 3 will determine the efficacy and mechanism of action of spliceosomal modulatory compounds in CMML PDXs based on spliceosomal gene mutation status. The significance of these studies is that they will create genetically and phenotypically accurate models of an aggressive form of cancer that is lacking preclinical models currently. Moreover, the health relatedness is that our studies will identify novel therapies for this condition, which lacks any effective therapies currently.